Bottom Line:
Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in the initiation of antitumor immune responses.In this study, we show that genetic modifications of a murine epidermis-derived DC line and primary bone marrow-derived DCs to express a model antigen beta-galactosidase (betagal) can be achieved through the use of a replication-deficient, recombinant adenovirus vector, and that the modified DCs are capable of eliciting antigen-specific, MHC-restricted CTL responses.We conclude that genetic modification of DCs to express antigens that are also expressed in tumors can lead to antigen-specific, antitumor killer cells, with a concomitant resistance to tumor challenge and a decrease in the size of existing tumors.

Affiliation: Division of Pulmonary and Critical Care Medicine, The New York Hospital-Cornell Medical Center 10021, USA.

ABSTRACTDendritic cells (DCs) are potent antigen-presenting cells that play a critical role in the initiation of antitumor immune responses. In this study, we show that genetic modifications of a murine epidermis-derived DC line and primary bone marrow-derived DCs to express a model antigen beta-galactosidase (betagal) can be achieved through the use of a replication-deficient, recombinant adenovirus vector, and that the modified DCs are capable of eliciting antigen-specific, MHC-restricted CTL responses. Importantly, using a murine metastatic lung tumor model with syngeneic colon carcinoma cells expressing betagal, we show that immunization of mice with the genetically modified DC line or bone marrow DCs confers potent protection against a lethal tumor challenge, as well as suppression of preestablished tumors, resulting in a significant survival advantage. We conclude that genetic modification of DCs to express antigens that are also expressed in tumors can lead to antigen-specific, antitumor killer cells, with a concomitant resistance to tumor challenge and a decrease in the size of existing tumors.

Figure 4: Survival advantage in mice immunized with modified XS52 cells after a tumor challenge. Animals were immunized with XS52 cells modified with Adβgal or AdNull. The experiment is similar to that depicted in Fig. 3, except that the animals were not killed but were followed for survival. The data is expressed as percent survival as a function of time. Survival for the mice immunized with XS52-Adβgal was significantly prolonged over the XS52-AdNull control, as determined by log-rank analysis of the Kaplan-Meier survival curves (P <0.0001).

Mentions:
The metastatic lung tumor model in this study was highly lethal, such that mice immunized with the negative control DCs (XS52-AdNull) succumbed to advanced pulmonary malignancy an average of two wk after tumor implantation (Fig. 4). In contrast, mice which had been preimmunized with XS52-Adβgal exhibited a markedly prolonged survival (P <0.0001, Fig. 4), consistent with the findings that XS52-βgal–immunized mice had far fewer lung metastases than the control treatment groups after a tumor challenge. Importantly, no protection was conferred by XS52-Adβgal immunization against CT26.WT tumor cells which did not express βgal (P >0.06; not shown), suggesting that the antitumor immunity generated by administration of the Adβgal-modified DCs was antigen (βgal)- specific.

Figure 4: Survival advantage in mice immunized with modified XS52 cells after a tumor challenge. Animals were immunized with XS52 cells modified with Adβgal or AdNull. The experiment is similar to that depicted in Fig. 3, except that the animals were not killed but were followed for survival. The data is expressed as percent survival as a function of time. Survival for the mice immunized with XS52-Adβgal was significantly prolonged over the XS52-AdNull control, as determined by log-rank analysis of the Kaplan-Meier survival curves (P <0.0001).

Mentions:
The metastatic lung tumor model in this study was highly lethal, such that mice immunized with the negative control DCs (XS52-AdNull) succumbed to advanced pulmonary malignancy an average of two wk after tumor implantation (Fig. 4). In contrast, mice which had been preimmunized with XS52-Adβgal exhibited a markedly prolonged survival (P <0.0001, Fig. 4), consistent with the findings that XS52-βgal–immunized mice had far fewer lung metastases than the control treatment groups after a tumor challenge. Importantly, no protection was conferred by XS52-Adβgal immunization against CT26.WT tumor cells which did not express βgal (P >0.06; not shown), suggesting that the antitumor immunity generated by administration of the Adβgal-modified DCs was antigen (βgal)- specific.

Bottom Line:
Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in the initiation of antitumor immune responses.In this study, we show that genetic modifications of a murine epidermis-derived DC line and primary bone marrow-derived DCs to express a model antigen beta-galactosidase (betagal) can be achieved through the use of a replication-deficient, recombinant adenovirus vector, and that the modified DCs are capable of eliciting antigen-specific, MHC-restricted CTL responses.We conclude that genetic modification of DCs to express antigens that are also expressed in tumors can lead to antigen-specific, antitumor killer cells, with a concomitant resistance to tumor challenge and a decrease in the size of existing tumors.

Affiliation:
Division of Pulmonary and Critical Care Medicine, The New York Hospital-Cornell Medical Center 10021, USA.

ABSTRACTDendritic cells (DCs) are potent antigen-presenting cells that play a critical role in the initiation of antitumor immune responses. In this study, we show that genetic modifications of a murine epidermis-derived DC line and primary bone marrow-derived DCs to express a model antigen beta-galactosidase (betagal) can be achieved through the use of a replication-deficient, recombinant adenovirus vector, and that the modified DCs are capable of eliciting antigen-specific, MHC-restricted CTL responses. Importantly, using a murine metastatic lung tumor model with syngeneic colon carcinoma cells expressing betagal, we show that immunization of mice with the genetically modified DC line or bone marrow DCs confers potent protection against a lethal tumor challenge, as well as suppression of preestablished tumors, resulting in a significant survival advantage. We conclude that genetic modification of DCs to express antigens that are also expressed in tumors can lead to antigen-specific, antitumor killer cells, with a concomitant resistance to tumor challenge and a decrease in the size of existing tumors.